The present invention relates to a process for producing trans-L-hydroxyproline. Trans-L-hydroxyproline is a known compound which is useful as a starting material for the synthesis of medicines such as the anti-inflammatory agent N-acetyl-hydroxyproline.
It is known that hydroxyproline can be produced by extraction from proteins such as collagen or by chemical synthesis. Examples of known chemical synthetic methods are synthesis from allyl bromide and diethylacetamidomalonic acid [Bull. Chem. Soc. Japan, 46, 2924 (1973)], synthesis from D-glutamic acid [Bull. Chem. Soc. Japan, 47, 1704 (1974)] and synthesis from glyoxal and oxaloacetic acid [J. Org. Chem., 42, 3440 (1977)].
However, these chemical synthetic methods are not suitable for industrial application because the yields of the product are low and the product is obtained as a mixture of four isomers. Accordingly, trans-L-hydroxyproline is generally produced by hydrolyzing a protein derived from an animal tissue such as collagen or elastin which contains trans-L-hydroxyproline in a large amount, followed by isolation through extraction. However, the hydrolyzate obtained by such method contains, in addition to trans-L-hydroxyproline, a variety of neutral amino acids such as glycine, L-proline, L-alanine and L-serine. Therefore, multiple purifying steps are required to isolate trans-L-hydroxyproline from these neutral amino acids.
Accordingly, a need exists for a less complex process for producing trans-L-hydroxyproline on an industrial scale. To this end, the present inventors have developed a process for readily purifying and isolating trans-L-hydroxyproline by culturing a microorganism in a culture medium containing a collagen hydrolyzate and decomposing amino acids other than trans-L-hydroxyproline in the culture medium.